Norsteroid derivatives



United States Patent 26,050 B-NORSTEROID DERIVATIVES James F. Kerwin,Broomall, Pa., assignor to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No Drawing. OriginalNo. 3,072,681, dated Jan. 8, 1963,

Ser. No. 849,166, Oct. 28, 1959. Application for reissue Oct. 8, 1965,Ser. No. 495,767

4 Claims. (Cl. 260343.2)

Matter enclosed in heavy brackets appears in the original patent butforms no part of this reissue specilication; matter printed in italicsindicates the additions made by reissue.

This invention relates to a new series of ring B modified steroidcompounds. More specifically this invention relates to B-norprogesteroneor testosterone derivatives.

These compounds have surprisingly retained activity qualitatively thesame as each parent compound despite such a radical change as making theB ring a 5 mem bered moiety. Therefore these compounds, for example,have progestational activity in the B-norprogesterone series or anabolicactivity in the B-nor-l7iz-alkyltcstosterone series. Each of thecompounds furthermore is useful as an intermediate for preparing morehighly substituted analogues in its respective therapeutic family ofcompounds.

The compounds of this invention, therefore, are unique in having a 5membered ring in the Bposition and are represented by the followingfundamental formula:

Formula I OH OH II CU; (int (CCU The compounds are prepared fromintermediates represented by the following formula:

R1 is or lowing series of reactions in which Ac is acyl preferablyacetyl.

"ice

EXAMPLE 1 A solution of 25.0 g. of pregnenolone acetate in 300 ml. ofglacial acetic acid is added to a solution of 22.8 g. of chromiumtrioxide in 90 ml. of aqueous acetic acid over 2.5 hours. After stirringfor 3 hours at about C., the reaction mixture is quenched with 20 m1. ofmethanol, then 1 l. of water. The quenched mixture is extracted withmethylene chloride. The organic extracts are combined and washed with 5%sodium carbonate until basic. The basic solutions are acidified withconcentrated hydrochloric acid and extracted into ether. The ether isevaporated to leave a yellow oil, 3-acetoxy-5-oxo5,6-seco-pregnan-ZO-on-G-oic acid.

The methylene chloride layer is Washed and evaporated to give7-keto-pregnenolone acetate, MP. l48-l50" C.

A mixture of 10.4 g. of the yellow oily acid, 50 ml. of anhydrouspyridine and 10 ml. of benzoyl chloride is reacted at room temperaturefor 49 hours then quenched in 400 ml. of water. The separated brown oilis extracted into ether. The washed extract is evaporated to give [3-acetoxy 5 hydroxy 5,6 seco 4 pregnen 6 oic acid. 5,6-lactone,] theIucmne intermediate, M.P 163- 165 C.

A sample of 2.7 g. of the lactone is heated at C. until the evolution ofgas ceases. The recrystallized residue, M.P. -121 C., isB-norpregnenolone acetate. A mixture of 2.9 g. of the acetate, 150 ml.of methanol, 3,5 g. of potassium carbonate and 25 ml. of water is heatedat reflux for 2 hours, partly evaporated under reduced pressure, dilutedwith water and filtered to give B-norpregnenolone, M.P. -141 C.

A mixture of 1.9 g. of the pregnenolone, 4.0 g. of aluminumisopropoxide, 200 ml. of anhydrous toluene and 10 ml. of cyclohexanoneis heated at reflux for 2 hours. The residue is taken into methylenechloride. The product isolated from the extract is B-nor-progestcrone,M.P. 140143 C.

EXAMPLE 2 A stirred solution of 25.0 g. of dehydroepiandrosteroneacetate, prepared by acetylation in pyridine with acetic anhydride, in400 ml. of glacial acetic acid is added to a solution of 22.8 g. ofchromium trioxide in 90 ml. of 50% aqueous acetic acid in 2 hours at55-60 C. The reaction mixture is quenched as in Example 1 then extractedwith methylene chloride which is in turn extracted with sodium carbonatesolution. The alkaline extracts are acidified with hydrochloric acid andextracted with ether to give 3 acetoxy [5 oxo]5,I7-di0x0 5,6seco-androstan-6 oic acid as a yellow oil. The ketone,7keto-dehydroepiandrosterone acetate, is obtained by working up themethylene chloride layer, M.P. 185187 C.

A mixture of 15.7 g. of the acid, 50 ml. of pyridine and ml. of benzoylchloride is reacted at room temperature for 41 hours. After quenching inwater and extraction with ether the desired [3-acetoxy-5-hydroxy-5,6-seco-4-androsten-6-oic acid, 5,6-lactone,] lactane intermediate, M.P.162164 C. is obtained. A sample of 10.8 g. of the lactone is heated at183 C. until gas evolution stops. After recrystallization from methanol,B-nor-dehydroepiandrosterone acetate, M.P. 140-142 C. is obtained.

EXAMPLE 3 A solution of 8.0 g. of B-nor-dehydroepiandrosterone acetateof Example 2 in 250 ml. of dry benzene is reacted with a slight excessof 3M methyl magnesium bromide in ether reagent (65-70 ml.) overminutes. After a reflux period of 2 hours the mixture is quenched overice, acidified with concentrated hydrochloric and extracted withmethylene chloride. After evaporation of the extracts andrecrystallization of the residue from acetone17amethyl-i7,8,3/8-dihydroxy-B-nor-S-androstene, M.P. 203- 204" C. isobtained.

A mixture of 5 g. of this compound, 10 g. of aluminum isopropoxide, 500ml. of anhydrous toluene and 27 ml. of cyclohexanone is heated at refluxfor 2 hours, cooled and washed. The organic layer is steam distilled.The residue is taken into methylene chloride which is dried, washed andevaporated to give B-nor-17-methyltcstosterone, M.P. 150153 C.

EXAMPLE 4 A solution of 2 g. of B-nor-dehydroepiandrosterone acetate,from Example 2 in 100 ml. of benzene is reacted EXAMPLE 5 A mixture of Sg. of potassium reacted with 100 ml. of a-amyl alcohol and 100 m]. ofdry ether is cooled and dry acetylene flushed through the mixture for 2hours. B-nordehydroepiandrosterone acetate (5 g.) is added and theflushing continued for 4 hours. The ice bath is removed and acetyleneflushing continued for 12 hours.

After addition of 10% ammonium chloride solution and 300 ml. of water,the organic layer is removed in vacuo. The remaining water is decanted.The residue is taken through benzene purified and recrystallized to giveB-norl7a-Cthi1lyl-17b hydroxydehydroepiandrosteronc. Reaction of 500 mg.of this compound with aluminum isopropoxide under Oppenauer conditionsas described above gives B-nor-17-ethinyltestosterone.

What is claimed is:

1. B-norprogesterone.

2. B-nor-l7u-ethinyltestosterone.

3. A compound of the formula:

in which R is a member selected from the group consisting of hydrogenand acetyl.

[4. A compound of the formula:

in which Ac is acetyL] 5. The t'aclone prepared by treating3-acct0xy-5-ox0- 5,d-secopregnurz-20-0n-6-0ic acid with benzoyl chloridein pyridine.

References Cited by the Examiner The following references, cited by theExaminer, are of record in the patented file of this patent or theoriginal patent.

UNITED STATES PATENTS 3,080,380 3/1963 Atwater 260343.Z

OTHER REFERENCES Karrer: Organic Chemistry, Elsevier, New York WALTER A.MODANCE, Primary Examiner.

JAMES A. PATTEN, Assistant Examiner.

5. THE LACTONE PREPARED BY TREATING3-ACETORY-5-OXO5,6-SECOPREGNAN-20-ON-6-OIC ACID WITH BENZOYL CHORIDE INPYRIDINE.